Project Summary Recent advances in treatment and management allow many patients suffering a spinal cord injury (SCI) to live for many years after their traumatic event. Moreover, given increased falls in the elderly, the risk of SCI has been increasing in that population. Recent evidence, including a large-scale longitudinal population-based study, indicates that isolated SCI (without concurrent brain injury) are at a high risk of dementia associated with substantial cognitive impairments. Yet little is known about the mechanisms of SCI-induced dementia or its relationship to age of onset or age-related neurodegenerative disorders such as Alzheimer?s disease (AD). This represents an unmet health-care challenge. Exosomes (Exo), containing microRNAs (miRs), proteins, and lipids from their originating cells, have emerged as potentially important regulators of secondary injury after SCI, not only locally but also systemically and in the brain. Exo release has also been hypothesized to contribute to the progression of AD. The purpose of this study is to identify the key mechanisms involved in critical yet largely ignored brain changes after SCI and test the hypothesis that SCI disrupts plasma Exo/miRs cargo content, ultimately promoting brain neuroinflammation through pro-inflammatory miRs leading to dementia, and physiologically-informed engineering of therapeutic Exo can be employed to counteract these effects. We will use young adult and aged animals to delineate the role of plasma Exo/miRs cargo as a key regulator of brain microglial activation and related down-stream injury mechanisms in SCI. Aim 1 will identify the molecular mechanisms of brain inflammation in SCI-mediated dementia. Multiple quantitative assessments of neuroinflammation and functional outcomes will be combined with characterization of plasma Exo/miRs cargo derived from sham or SCI mice to test the hypothesis that SCI-induced release of Exo into the blood contributes to brain neuroinflammation through pro-inflammatory miRs leading to cognitive deficits. Aim 2 will assess the influence of aging on SCI-mediated dementia. Aged mice and 3xTg AD mice will be used to address the influence of age as well as pre-existing dementia risk on SCI-mediated dysregulation of Exo/miRs cargo, neuroinflammation in the brain, and associated cognitive impairments. Aim 3 will develop physiologically-informed engineering of therapeutic Exo for preventing and controlling dementia progression after SCI. We will optimize approaches to exert control over Exo/miRs cargo and delivery informed by brain-specific Exo communication. Engineered Exo will be applied to young adult, aged, and AD mice after SCI, neuroinflammation, neurodegeneration, and functional outcomes will be assessed. The information gained from these highly significant and innovative studies will have an important positive impact through identifying the key mechanisms involved in critical yet largely ignored brain changes after SCI and through the development of novel potential therapeutic interventions.